Prediction and evaluation of deleterious and disease causing non-synonymous SNPs (nsSNPs) in human NF2 gene responsible for neurofibromatosis type 2 (NF2)

Abstract

The majority of genetic variations in the human genome that lead to variety of different diseases are caused by non-synonymous single nucleotide polymorphisms (nsSNPs). Neurofibromatosis type 2 (NF2) is a deadly disease caused by nsSNPs in the NF2 gene that encodes for a protein called merlin. This study used various in silico methods, SIFT, Polyphen-2, PhD-SNP and MutPred, to investigate the pathogenic effect of 14 nsSNPs in the merlin FERM domain. The G197C and L234R mutations were found to be two deleterious and disease mutations associated with the mild and severe forms of NF2, respectively. Molecular dynamics (MD) simulations were conducted to understand the stability, structure and dynamics of these mutations. Both mutant structures experienced larger flexibility compared to the wildtype. The L234R mutant suffered from more prominent structural instability, which may help to explain why it is associated with the more severe form of NF2. The intramolecular hydrogen bonding in L234R mutation decreased from the wildtype, while intermolecular hydrogen bonding of L234R mutation with solvent greatly increased. The native contacts were also found to be important. Protein–protein docking revealed that L234R mutation decreased the binding complementarity and binding affinity of LATS2 to merlin, which may have an impact on merlin’s ability to regulate the Hippo signaling pathway. The calculated binding affinity of the LATS2 to L234R mutant and wildtype merlin protein is found to be 21.73 and −11 kcal/mol, respectively. The binding affinity of the wildtype merlin agreed very well with the experimental value, −8 kcal/mol. Communicated by Ramaswamy H. Sarma